The goal of the project is to understand the role of matrix-degrading metalloproteinases (MMPs) in the progression of chemically-induced mouse cutaneous squamous cell carcinoma (SCC). In the early stages of SCC progression, stromelysin-1/transin is expressed in the stromal component of benign and malignant tumors. However, when squamous carcinomas convert to spindle carcinomas with a concomitant increase in metastatic potential, stromelysin-1 is expressed in the neoplastic cells as well. We will test the hypothesis that host/tumor interactions manifest by stromal cell expression of stromelysin-1 in early stages of tumor progression contributes to the growth of the tumor, and spindle cell expression of stomelysin-1 during late stages of tumor progression contributes to tumor metastasis. Transgenic and gene """"""""knockout"""""""" mouse model systems in which the expression of stromelysin-1 has been abrogated or selectively enhanced will be employed for these studies. In addition, squamous and spindle carcinoma-derived cell lines will be injected into thymectomized wildtype or stromelysin-1 null mice to distinguish between effects of stromal and tumor MMP production specifically. We will also generate mice in which the collagenase gene and/or the stromelysin-2 gene in addition to the stromelysin-1 gene has been ablated to test for combinatorial effects of MMP family members on SSC tumor progression. We propose that the expression of stromelysin-1 in spindle tumor cells is a reflection of important cellular or molecular changes that play a causal role in the progression to a metastatic phenotype. Stromelysin-1 gene expression provides a useful tool to identify the molecular basis of such factors. Based on current knowledge of the regulation of stromelysin-1 gene expression, squamous and spindle tumor -derived cell lines will be compared for alterations in AP-1 binding complexes and the levels and phosphorylation state of members of the Fos and Jun families of transcription factors. The possibility that novel suppressor genes can be cloned using stromelysin-1 gene expression as an indicator will be explored. The studies proposed in this application could provide important new insights into molecules mediating host/tumor interactions and tumor invasion and metastasis in a well defined model of tumor progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA046843-13S1
Application #
6222399
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1988-03-01
Project End
2001-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
13
Fiscal Year
2000
Total Cost
$69,869
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
McCawley, Lisa J; Crawford, Howard C; King Jr, Lloyd E et al. (2004) A protective role for matrix metalloproteinase-3 in squamous cell carcinoma. Cancer Res 64:6965-72
Leite-Browning, Maria L; McCawley, Lisa J; Jahnen-Dechent, Willi et al. (2004) Alpha 2-HS glycoprotein (fetuin-A) modulates murine skin tumorigenesis. Int J Oncol 25:319-24
Leite-Browning, Maria L; McCawley, Lisa J; Choi, Oksoon H et al. (2002) Interactions of alpha2-HS-glycoprotein (fetuin) with MMP-3 and murine squamous cell carcinoma cells. Int J Oncol 21:965-71
Hulboy, D L; Matrisian, L M; Crawford, H C (2001) Loss of JunB activity enhances stromelysin 1 expression in a model of the epithelial-to-mesenchymal transition of mouse skin tumors. Mol Cell Biol 21:5478-87
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Haro, H; Crawford, H C; Fingleton, B et al. (2000) Matrix metalloproteinase-3-dependent generation of a macrophage chemoattractant in a model of herniated disc resorption. J Clin Invest 105:133-41
Nelson, A R; Fingleton, B; Rothenberg, M L et al. (2000) Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol 18:1135-49
Crawford, H C; Matrisian, L M; Liaw, L (1998) Distinct roles of osteopontin in host defense activity and tumor survival during squamous cell carcinoma progression in vivo. Cancer Res 58:5206-15
Rudolph-Owen, L A; Matrisian, L M (1998) Matrix metalloproteinases in remodeling of the normal and neoplastic mammary gland. J Mammary Gland Biol Neoplasia 3:177-89
Hulboy, D L; Rudolph, L A; Matrisian, L M (1997) Matrix metalloproteinases as mediators of reproductive function. Mol Hum Reprod 3:27-45

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